The use of pADPRT inhibitory compounds have been reported for treating cancer and viral infections. Examples of these methods are described in U.S. Pat. Nos. 5,464,871, 5,473,074; 5,482,975, 5,484,951; 5,516,941, and 5,583,155, the disclosures of which are incorporated herein by reference.
In the published literature, 5-iodo-6-amino-1,2-benzopyrone (INH.sub.2 BP), a novel inhibitor of the nuclear enzyme poly-ADP ribose polymerase (PADPRT) has recently been shown to inhibit in vivo tumorigenicity in a Ha-ras transfected endothelial cell line (Bauer et al., Int. J. Oncol. 8:239-252 (1995) and Bauer et al., Biochimie 77:347-377 (1995)). Treatment with INH.sub.2 BP has also resulted in changes in topoisomerase I and II and MAP kinase activity Based on the effects observed, a hypothesis regarding the potential use of INH.sub.2 BP in the therapy of cancer has been put forward.
Malignant growth and inflammatory processes may feature the activation of certain common cellular signal transduction pathways, e.g., MAP kinase (Kyriakis et al., J. Biol. Chem. 271:24313-24316 (1996) and Ferrell, TIBS 21:460-466 (1996)). Chronic inflammation frequently leads to carcinogenic transformation, as demonstrated, for example, in the case of the intestine. In our study, the production of multiple proinflammatory mediators was induced by bacterial lipopolysaccharide (endotoxin, LPS). LPS is known to induce a multitude of cellular reactions and triggers a systemic inflammatory response. LPS-induced pro-inflammatory mediators include tumor necrosis factor alpha (TNF), interleukin-1, interferon-gamma, whereas antiinflammatory mediators include interleukin-10 (IL-10) and interleukin-13 (Deltenre et al., Acta Gastroenterol Belg. 58:193-200 (1995), Beutler, J. Invest. Med. 42:227-35 (1995), Liles et al., J. Infect Dis. 172:1573-80 (1995), and Giroir, Critical Car. Med. 21:780-9 (1993)). As a consequence of the production of these inflammatory cytokines, LPS initiates the production of inflammatory free radicals (oxygen-centered, such as superoxide, and nitrogen-centered radicals, such as nitric oxide (NO) and of prostaglandins (Nathan, FASEB J. 6:3051-3064 (1992), Vane, Proc. Roy. Soc. Lond B 343:225-246 (1993), and Szabo, New Horizons 3:3-32 (1995)). The production of NO in inflammation is due to the expression of a distinct isoform of NO synthase (iNOS), while the production of inflammatory cytokines is explained by the expression of a distinct isoform of cyclooxygenase (cyclooxygenase-2, COX-2), iNOS, COX-2, as well as other pro-inflammatory cytokines and free radicals which play an important role in the LPS-induced inflammatory response. Moreover, NO (or its toxic byproduct, peroxynitrite), has been implicated as a key mediator leading to the transformation of the inflammatory response into a carcinogenic process (Bartsch et al., Pharmacogenetics 2:272-7 (1994), Liu et al., Carcinogenesis 15:2875-7 (1992) and Ohshima et al., Mutation Res. 305:253-64 (1994)).
There are a multitude of intracellular processes which precede the production of proinflammatory mediators. Activation of tyrosine kinases (Levitzki, A., Eur. J. Biochem. 226:1-13 (1994), Novogrodsky et al., Science 264:1319-22 (1994), Marczin et al., Am. J. Physiol. 265:H1014-1018 (1993)), mitogen-activated protein kinase (MAP kinase, Matsuda et al., J. Leukocyte Biol. 56:548-53 (1994), L'Allemain, Progr. Growth Factor Res. 5:291-334 (1994), and Cowley et al., Cells 77:841-52 (1994)); and the nuclear factor kappa B (NF-kB) pathway (Baeuerle et al., Ann. Rev. Immunol. 12:141-79 (1994), Schreck et al., Free Radical Res. Comm. 17:221-37 (1992) and Muller et al., Immunobiol. 187:233-56 (1993)) are recognized as important factors in the inflammatory response and contribute to the expression or production of inflammatory mediators.